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3,058,984 3 BISMONQCARBGCYCLIC ARYL)-METHYL- ENETROPANE EPOXIDES AND PREPARA- TIUN THEREOF Sydney Archer, Bethlehem, and Malcolm R. Bell, North Greenbush, N.Y., assignors to Sterling Drug Inc, New York, NFL, a corporation of Delaware N Drawing. Qriginal application Apr. 30, 1958, Ser. No. 731,857. Divided and this application Nov. 23, 1959, Ser. No. 850,960

CH2CH-OH2 1) (1) COOR" wherein R represents hydrogen, a lower-aliphatic hydrocarbon, monocarbocyclic aryl substituted lower-aliphatic hydrocarbon, or a monocarbocyclic arylamino substituted lower-aliphatic hydrocarbon radical, R represents hydrogen, a lower-alkoxy radical, the hydroxy radical or a carboxylic acyloxy radical, and R" represents a loWer-alkyl radical.

In the above general Formula I, R represents a hydrogen atom or a substituent selected from lower-aliphatic hydrocarbon, monocarbocyclic aryl substituted loweraliphatic hydrocarbon, and monocarbocyclic arylamino substituted lower-aliphatic hydrocarbon radicals. When R stands for a lower-aliphatic hydrocarbon radical it represents saturated or unsaturated radicals, i.e., loweralkyl, loWer-alkenyl, or lower-alkynyl having from one to about eight carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tertiary-butyl, hexyl, octyl, vinyl, l-propenyl, 2-propenyl (allyl), Z-butenyl, ethynyl, propargyl, and the like.

When R represents a .monocarbocyclic aryl substituted lower-aliphatic hydrocarbon radical, it stands for the same type of lower-aliphatic radicals as described above substituted by a phenyl radical or a phenyl radical having one or more substituents such as hydroxy, fluoro, chloro, bromo, iodo, nitro, amino, lower-alkoxy, loWer-alkylamino or lower-carboxylic acylamino. A preferred class of monocarbocyclic aryl radicals comprises phenyl and phenyl substituted by from one to three substituents selected from hydroxy, fluoro, chloro, bremo, iodo, nitro, amino, lower-alkoxy, lower-alkylamino and lower-carboxylic acylamino. Thus R can represent such groups as benzyl, 2-phenylethyl, 3-phenylpropyl, einnamyl, paminophenethyl, p-methoxyphenethyl, p-chlorophenethyl, 3,4,5-trimethoxyphenyl, and the like.

When R represents a monocarbocyclic arylamino substituted lower-aliphatic hydrocarbon radical, the monocarbocyclic aryl and lower-hydrocarbon moieties have the same meanings as given above, but are separated .by an imino grouping, NH, and R in this instance represents such groups as Z-phenylaminoethyl, S-phenylaminopropyl, 3 phenylamino 2 propenyl, Z-(p-azninophenyla-mino) ethyl, and the like.

In the above general Formula I, R represents a hydrogen atom or a loWer-alkoxy, hydroxy or carboxylic acyloxy radical. The lower-alkoxy radicals have preferably from one to about four carbon atoms, thus including such radicals as methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like. The carboxylic acyloxy radicals are preferably derived from carboXylic acids having from one to about ten carbon atoms, and having a molecular weight less than about 250. Representative of the acyl radicals which can be present are lower-alkauoyl radicals, e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, caproyl, heptanoyl, octanoyl, decanoyl, and the like; carboXy-lower-alkanoyl radicals, e.g., succinyl 8-carboxypropionyl); cycloalkyl-lower-alkanoyl radicals, e.g., ,B-cyclopentylpropionyl, S-cyclohexylpropionyl, and the like; monocarbocyclic aroyl radicals, e.g., benzoyl, p-toluyl, p-nitrobenzoyl, 3,4,5-trimethoxybenzoyl, and the like; and monocarbocyclic aryl-lower-alkanoyl or -alkenoyl radicals, such as phenylacetyl, ,B-pheny-lpropionyl, einnarnoyl, and the like.

In the above general Formula I, R" represents a hydrogen atom or a lower-alkyl radical, the latter having preferably from one to about six carbon atoms, thus including such radicals as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

The preparation of the compounds of the invention is delineated by the following flow-sheet:

loweralkancl O-lcwer-alkyl 1-2 hours (room temp.)

' $40 Halli, tag

vI (R=H or lower-alkoxy) Olin-- onr-on-ogo R-N ho Zn Oh, ACRO 10 or more hours (room temp.)

VII (R=H or lower-alkoxy) arsena gentle heating may be 3 1 (L R, iiiaeaq HGl-HOAc 100 C dium to the cor-responding carboxylic acid, 3-hydroxy-3- caiboxy-S-R-nortropane (IV). The acid (IV) is esterified with a lower-alkanol under acid conditions to the lower-alkyl ester, 3-hydroXy-3-carbo-loWer-alkoXy-8-R- nortropane (V).

The hydroxy ester (V) is subjected to reaction with phenyllithium or a monocar bocyclic arylmagnesium halide, e.g., phenylmagnesium halide, or a 3-lower-a1koxy derivative thereof, and the intermediate organometallic complex is hydrolyzed to produce a 3- hydroXy- 3-[bis- (monocarbocyclic aryl)hydroxymethyl] 8-R-nortropane (VI). The reaction is carried out under anhydrous condit-ions in an inert solvent such as ether, benzene, toluene or the like, and takes place at room temperatures, although applied if desired to accelerate the reaction. a

The glycol (VI) when treated at room temperature with zinc chloride and acetic anhydride first dehydrates to give an epoxide of a 3-bis(rnonocarbocyclic aryl)methylene-8- R-nortropane (VII) and then rearranges to a 3-(mono carbocyclic aryl) -3-(monocarbocyclic aroyD-S-R-nortropane (VIII). The epox'ide (VII) can beisolated if the reaction mixture is worked up, after about one to two hours, whereas rearrangement to the ketone (VIII) is essentially complete if the reaction mixture is allowed to stand for at least about ten hours before working up.

The next step is the conversion of the ketone (VIII) to its oxime, a 3-(1'nonocarb0cyclic -aryl)-3'-(aisonitroso monocarbocyclic arylmethyl)-8-R-nortropane (IX) which is accomplished by heating the ketone with an acid-addition salt of hydroxyl-arnine in the presence of a base. Preferred bases are weak organic bases such as pyridine and the reaction is carried out in an inert solvent such as ethanol, at a temperature between about 50 C. and 150 C., in which case the oxirne is obtained directly in the form of its acid-addition salt.

The conversion of the oxime (IX) to a 3-(monocarbocyclic. aryl)-3-carboXy-8-R-nortropane (X) is efiected by heating a solution of the oxime in acetic acid saturated with dry hydrogen chloride at a temperature between about 50 C. and 150 C. The transformation involves I a Beckmann rearrangement followed by cleavage of the intermediateanilide having the grouping -CONHC H R in the 3-position, as confirmed by the isolation of aniline from the reaction mixture in the case Where R is H.

The final step is an esterification of the acid (X) by treating. it with a iower alkanol in the presence of a strong acid, giving a 3-(monocarbocyclic aryl) 3.-.( carbo-loweralkoxy)-8 R-nortropane (1). The esterification takes place at room temperature or above.

The ketones of Formula VIII can be. reduced catalyticaily or with lithium aluminum hydride to produce the corresponding hydroxy compounds, 3-(monocarbocyclic aryl) -3-(monocarbocyclic aryl-hydroxymethyl) -8-R-nortropanes (XI) v.

n .OH 7 oH, JnoH ,on

! R N OHz-hH-hE The compounds of Formula XI in the form of their acidaddition or quaternary ammonium salts are useful as anticholingeric agents.

An alternative approach to the compounds of the invention of Formula I is set forth in the following flowsheet (R"' represents a loWer-alkyl radical and R has the meaning given above):

CHg--OHCH5 OH NaNH: NH:

t 7 RI XVI (R =E 01 lower alkoxy) A 3-hydroXy-3-carbo=loweralkoxy=8-R-nortropane of structure V is converted to thecorresponding amide, 3-hydroxy-3-carbamyl-8-R-nortropane (XII) by treating with sodium amide in liquid ammonia. The amide XII is then subjected to a Grignard reaction with arlower-alkylmagnesium halide, the reaction stopping readily at the ketone stage togive a 3-hydroxy-3-lower-alkanoyl-8 R- nortropane (XIII). The latter is then subjected to a second Grignard reaction with phenyllithium, phenylmagnesium halide or a 3-lower-alkoxyphenylrnagnesium halide 'torproduce a 3-hydroXy-3-[-lower-alkyl(-mono-carbocyclic aryl)hydroxymethyl] S-R-nortropane (XIV); The structure XIV belongs to the same class of compounds as structwo VI and they can be represented by a single formula as follows:

wherein R represents hydrogen or a lower-alkoxy radical, Y represents a loWer-alkyl or 3-R-phenyl radical, and R has the same meaning as given above.

The diol XIV is then converted to the desired 3-(monocarbocyclic aryl)-3-lower-alkanoyl-8-R-nortropane (XV) by treatment with zinc chloride and acetic anhydride at room temperature for ten or more hours, analogously to the conversion of VI (or VII) to VIII. The structure XV belongs to the same class of compounds as structure VIII and they can be represented by a single formula as follows:

CH2(|IHCH2 COY R-E' I H; H-GH,

XVIII wherein R represents hydrogen or a lower-alkoxy radical,

Y represents a lower-alkyl or 3-R-phenyl radical and R has the same meaning as given above.

The ketone XV is then converted to its oxime, a 3- (monocarb ocyclic aryl) -3-( l-isonitroso-lower-alkyl -8-R- nortropane (XVI), by treatment with hydroxylamine, analogously to the conversion of VIII to IX. The structure XVI belongs to the same class of compounds as structure IX and they can be represented by a single formula as follows:

N011 CHg-CHCH/q( Y R-E l GH2 HCH2 XIX wherein R represents hydrogen or a lower-alkoxy radical, Y represents a lower-alkyl or a 3-R-phenyl radical, and R has the same meaning as given above.

The oxime XVI is then subjected to the Beckmann rearrangement by heating it with hydrochloric and acetic acid at about 100 C., analogously to the conversion of IX to X, and the structure X is again produced.

The ketones of Formulas VIII and XV, wherein R represents hydrogen or the methyl radical, when in the form of their acid-addition salts exist largely in the tautorneric carbinol-amine form, viz.:

I C-Y GEE-(37$! l El. 3/ X- 1 1 1X3 The foregoing structure was established from consideration of the infrared spectra of said ketones. In the case of compounds wherein R is hydrogen, the free bases can also exist in the carbinolamine form. Although the compounds of Formulas VIII and I are named and their structures depicted as ketones throughout this description, it is to be understood that the carbinolamine tautomeric forms are also contemplated as part of the invention.

The compounds of the invention of Formula I wherein R represents an organic radical can be prepared from the compounds wherein R represents hydrogen by reacting the latter with a halide, R-X, wherein X is halogen, in the presence of a basic condensing agent, or acid-acceptor, such as sodium carbonate, sodium methoxide, sodium amide, sodium hydride, or the like. This N-alky-lation procedure can be efiected at any stage in the synthesis, but preferably upon compounds I or V (R=H).

The compounds of the invention wherein R represents hydrogen can be prepared directly from notropincne (II, R=H) according to the above flow-sheet. Alternatively, they can be prepared by reacting a compound wherein R is methyl with cyanogen bromide and then treating the resulting N-cy-ano compound with acid or base.

The compounds of Formulas 1, VIII, X and XV wherein R is a hydroxy radical are prepared by deallrylation of the corresponding compounds wherein R is a loweralkoxy radical. The dealkylation is carried out by heating the alkoxy compound with hydrogen bromide or hydrogen iodide in water or acetic acid solution, or with pyridine hydrochloride or hydrobromide at about 200 C. If a compound of Formula I where R is hydroxy or acyloXy is desired, the dealkylation is preferably carried out on a compound of Formulas VIII, X or XV where R is lower-alkoxy, and the result-ing phenolic compound carried through the necessary subsequent steps to produce I (R is OH). The compounds wherein R is a carboxylic acyloxy radical are prepared by esterifying the compounds wherein R is hydroxy by reacting the latter with the appropriate acid anhydride or acid halide.

The compounds of Formulas VI to X, inclusive, XII to XVI, inclusive, and I can exist in two stereochemical forms, depending upon the spatial arrangement of the groups at C with respect to the remainer of the molecule. The sequence of steps shown in the first flow-sheet leads to compounds which will be designated the ,B-scries. The other stereochemical series, to be designated the aseries can be reached by treating the glycol V1 with acetic anhydride in the absence of zinc chloride which leads to the epoxide VII of the (it-series. The epoxide VII of the wseries can then be carried through the same series of reactions to produce the compounds VIII, IX, X and I of the a-series.

The novel compounds disclosed herein are useful in the free base form or in the form of acid-addition or quaternary ammonium salts, said salts also being within the purview of the invention. The preferred type of salts are pharmacodynamically acceptable salts, that is, salts whose anions are relatively innocuous to an animal organism in pharmacodynamic doses of the salts, so that the beneficial physiological properties inherent in the direc base are not vitiated by side-effects ascribable to the anions. Appropriate acid-addition salts 'are those derived from mineral acids such as hydrochloric acid, hydrobronnc acid, hydriodic acid, nitric acid, sulfuric acid and phosphoric acid; and organic acids such as acetic acid, citric acid, lactic acid, and tartaric acid. The quaternary ammonium salts are obtained by the addition of esters having a molecular weight less than about 200 to the free base form of the compounds. A preferred class of esters comprises alkyl, alkenyl or aralkyl esters of inorganic acids or organic sulfonic acids, and include such compounds as methyl chloride, methyl bromide, methyl iodide, ethyl bromide, propyl chloride, 2-hydroxyethyl bromide, allyl chloride, allyl bromide, methyl sulfate, methyl benzenesulfonate, methyl p-toluenesulfonate, benzyl chloride, benzyl bromide, and substituted benzyl halides, such as pchlorobenzyl chloride, p-nitrobenzyl chloride, o-chlorobenzyl chloride, p-methoxybenzyl chloride, and the like.

The acid-addition salts are prepared either by dissolving the free base in an aqueous solution containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.

preferred, all acid-addition salts are within the scope of our invention. All acid-addition salts are useful as sources of the free base form even if the particular salt per se is notdesired as the final product, as for example when the salt is formed for purposes of purification or identification, or when it is used as an intermediate in preparing a pharmacodynamically acceptable salt by ion exchange procedures. All crystalline salts are also useful as characterizing derivatives of the free bases.

The molecular structures of the novel compounds herein disclosed are established by their mode of synthesis and corroborated by the correspondence of calculated and found values for the elementary analyses for representa-- tive examples. The structures are further confirmed by ultraviolet and infrared spectral data proving the presence 'of the various functional groups.

The compounds of our invention having the general Formula I possess valuable pharmacodynamic properties,

in particular, analgesic activity. For example, when tested intraperitoneally in rats 'by the Bass-Van der Brook modification of the DAmour-Smith method, 3-phenyl-3- carbethoxytropane hydrochlorideEI; R is CH R isH, R" is C H fi-series], was found to be approximately two and one-quarter times as active as meperidine hydrochloride as an analgesic. The former'compound has an intravenous toxicity (LD in rats of 12.6i1.6 mg./kg. of body weight, and is very well tolerated by adults rhesus monkeys when administered intramuscularly in doses of 12 and 18 mg./kg. No depression of the respiratory rate or convulsions were observed in monkeys following administration of 3-pheny1-3-carbethoxytropane hydrochloride at doses as high as 18 mg./kg., whereas meperidine hydrochloride caused slight to moderate respiratory depression of one to three hours duration in monkeys when administered intramuscularly in single,'daily doses of 6.4 and 12.8 mg./kg. v

The compounds of Formula -I can be prepared for use by formulation in the same manner as meperidine, e.g., in aqueous or aqueous-ethanol menstruum, or in. solid was removed by filtration and washed with ether. The dark red filtrates were decolorized with activated charcoal, dried over anhydrous sodium sulfate, and the resulting solution was treated directly with an excess of alcoholic hydrogen chloride which caused separation of a nearly colorless crystalline powder. The latter was collected and dried at 60 C. in a vacuum oven for fifteen hours, giving 167 g. of 3-(diphenylhydroxymethyl)pseudotropine hydrochloride, M.P. 279.5-280.5 C. (decomposition) (corrected) after two recrystallizations from a methanolether mixture. Analysis.- Calcd. for CZIHZENOZ-HCILC, 70.08; H, 7.28; Cl, 9.85. Found: C, 69.99; H, 7.39; Cl, 9.74.

A sample of the hydrochloride was treated with aqeuous sodium carbonate, and the resulting free base was collected and recrystallized three times from hexane, giving 3-(diphenylhydroxymethyl)pseudotropine, M.P. 1l6-117 C. (uncorr.).

Analysis.-Calcd. for C H NO C, 77.99; H, 7.79; N, 4.33. Found: C, 77.93; H, 7.85; -N, 4.29.

EXAMPLE 2 S-Benzhydrolidenetropan Epqxide [VII; R is CH R is r H, ,B-series] Fused, powdered zinc chloride (10 g.) was added all at once to a stirred suspension of 10 g. of S-(diphenylhydroxymethyDpseudotropine hydrochloride (Example 1) in 25 ml. of acetic anhydride at room temperature. Within fifty minutes the reaction mixture became homogeneous. After stirring for eighty minutes the dark brown solution was poured into a solution of 25 g. of sodium hy- "droxide in 200 ml. of water. The tan colored solid which separated was collected, dried and extracted with 250 ml. of boiling hexane. Upon evaporation of the extract to a volume of 100 ml. and cooling there separated 4.7 g. of crystalline powder, M.P. l55-l66 C. Concentration of the filtrate gave an additional 1.0 g., M.P. ISO-161 C. The crops were combined and recrystallized from 30 ml. of boiling methanol to give 4.3 g. of 3-benzhydiylidenetropane epoxide in the form of colorless plates, M.P. 166-1665 C. (uncorr.).

AnalysiS.-Calcd. for C I-I NO: C, 82.55; H, 7.59;

' N, 4.59. Found: C, 32.32; H, 7.65; N, 4.04.

form, e.g'.,tablet or powder. The tablet formulation can 7 be prepared using conventional excipients, and the pow EXAMPLE 1 3-(Diphenylhydroxymethyl) Pseudotropine Hydrochloride V V, [VI; R is CH R is-H] A solution of 100g. of r-ecgonine methyl ester [V; R is CH in 325 ml. of tetrahydrofuran was added during a period of twenty minutes to a stirred solution of phenyllithium (prepared from 316 g. of bromdbenzene and 27.9 g. of lithium wire) in one liter of ether. -Vigorousreflux accompanied the addition and stopped abruptly when the addition was complete. The reaction'mixture was stirred and refluxed for one hour, then cooled and treated with 300 ml. of water. The solidmaterial which precipitated The hydrochloride salt of 3-benzhydrylidenetropane epoxide was prepared by addition of an excess of alcobromide pellet exhibited corbonyl or hydroxyl type absorption in the infared spectrum. The ultraviolet spectrum of the free base showed an extinction coeflicient of 13,400 and a maximum at 220 m plus Weak absorption peaks at 250-260 mg.

EXAMPLE 3 3-Phenyl-3- Berizoyltropane [VHI; R is CH R is H, fi-series'] (a) Method 1 [fr0m 3-(diphenylhydroxymethyl) pseud0tr0pine].-Fused powdered zinc chloride (98 g.)'was added all at once tow a stirred suspension of 98 g. of 3- was collected and extracted once with one liter of methylene dichloride. lThe filtrate was extracted three 9 times with 200 ml. portions of methylene dichloride. The methylene dichloride extracts were dried and concentrated, and the residual oil crystallized from 600 ml. of hexane. The 48.5 g. of 3-phenyl-3-benzoyltropane thus obtained had the MP. 121-122.5 C. (uncorr.) when recrystallized from 700 ml. of hexane.

Analysis.Calcd. for C H NO: C, 82.55; H, 7.59; N, 4.59. Found: C, 82.87; H, 7.43; N, 4.57.

The hydrochloride salt of 3-phenyl-3-benzoyltropane was obtained by treating an ether solution of a sample of the free base with an excess of alcoholic hydrogen chloride. The hydrochloride had the M.P. 249-251 C. (corn) when recrystallized from absolute ethanol.

Analysis.Calcd. for C21H23NO-HC1I C, 73.77; H, 7.07; Cl, 10.37. Found: C, 73.50; H, 6.98; Cl, 10.13.

The methiodide salt of 3-phenyl-3-benzoyltropane was prepared by treating an acetone solution of the free base with an excess of methyl iodide. The methiodide salt separated directly from solution and had the MP. 233.5- 2375 C. (corn);

Analysis.Calcd. for C22H26INO: C, 59.06; H, 5.87; I, 28.37. Found: C, 59.17; H, 5.60; I, 28.19.

The methiodide salt of 3-phenyl-3-benzoyltropane was found to have an anticholinergic activity 6.8% that of atropine sulfate. l-ts intravenous toxicity in mice (AL Was 9 mg./kg. of body weight.

(b) Metho d 2 [from 3-benzhydryliden'etropane ep xide].A mixture of 3-benzhydrylidenetropane epoxide hydrochloride (Example 2, prepared from 2.0 g. of the free base), 2 g. of fused, powdered zinc chloride and ml. of acetic anhydride was stirred at room temperature for fifty-four hours. The reaction mixture was worked up according to the procedure described above in Method 1, giving 1.1 g. of 3-phenyl-3-benzoyltropane which upon recrystallization from hexane melted at l21.5122 C., undepressed upon admixture with the product obtained above by Method 1.

EXAhdPLE 4 3-Przenyl-3-(Phenylisonitrosomethyl) T r pmZe Hydrochloride [IX; R is CH R is H, fl-series] EXAMPLE 5 -Plzenyl-3-Carboxytropan'e Hydrochloride [X; R

is CH R is H, fi-series] A suspension of g. of 3-phenyl-3-(phenylisonitrosomethyl)tropane hydrochloride (Example 4) in 75 ml. of acetic acid at 0 C. was saturated with dry hydrogen chloride gas. The solution was enclosed in a pressure bottle and heated on a steam bath for seventy minutes. At the end of this period the bottle was cooled, opened, and the solvent was evaporated in vacuo on a steam bath. The residue was dissolved in 50 ml. of Warm methanol, and 200 ml. of ether was added to cause separation of a solid product. The latter was collected and recrystallized from 75 m1. of methanol and 130 ml. of ether, giving 4.5

g. of 3-phenyl-3-carboxytropane hydrochloride, MP. 224- 225 C. (dec.) (corn) after a second recriystallization from the same solvents.

Analysis.Calcd. for C H NO .HCl: C, 63.93; H, 7.16; Cl, 12.58. Found: C, 63.80; H, 7.30; CI, 12.55.

It was found that in the preceding preparation the pressure bottle could be dispensed with and the reaction 10 accomplished by heating the reaction mixture at C. for two hours at atmospheric pressure while passing in dry hydrogen chloride.

In another run, aniline was isolated from the mother liquors by steam distillation, thus proving that the starting oxime had undergone a Beckmann rearrangement, followed by cleavage of the intermediate amide.

EXAMPLE 6 3-Phenyl-3-Carbetlz0xytropane Hydrochloride [*I; R is CH R is H, R is C H fi-series] A solution of 1.0 g. of 3-phenyl-3-carboxytropane hydrochloride (Example 5) in 40 ml. of absolute ethanol was saturated with dry hydrogen chloride and allowed to stand at room temperature for six days. The reaction mixture was then concentrated in vacuo, and the solid residue was recrystallized from 15 ml. of absolute ethanol and ml. of anhydrous ether, giving 0.9 g. of 3-ph'e11yl- S-carbcthoxytropane hydrochloride in the form of colorless needles, MP. 18719l C. (dec.)(corr.)

Analysis-Calcd. for C H NO .HCl: C, 65.90; H, 7.81; Cl, 11.49. Found: C, 65.82; H, 7.81; C1, 11.28.

By replacement of the ethanol in the preceding preparation by methanol, l-propanol, 2propanol, l-but'anol or l-hexanol, there can be obtained, respectively, 3-p'heny l- 3-carbomethoxytropane hydrochloride [1; Ris CH R is H, R" is CH 3-phenyl-3-carbopropoxytropane hydrochloride [1; R is CH R is H, R is (CH Ci-I 3- phenyl-3-carboisopropoxytropane hydrochloride [1; R is CH R is H, R" is CH(CH 3-phen-yl-3-carbobutoxytropane hydrochloride [1; R is CH R is H, R" is (CH CH or 3-phenyl-3-carbohexoxytropane hydrochloride [1; R is CH R is H, R" is (CH CH The methobromide salt of 3-phenyl-3-carbethoxytropane was prepared by treating an acetonitrile solution of the free base with an excess of methyl bromide. The product separated directly from the solution and had the M.P. 206207.5 C. (uncorr.) after recrystallization from an isopropyl alcohol-ether mixture.

Analysis.Calcd. for 'C H NO 'Br: C, 58.19; H, 7.12; Br, 21.70. Found: C, 58.44; H, 7.13; Br, 21.63.

3-phenyl-3-carbethoxytropane hydrochloride can be reacted with a molar equivalent amount of a base, e.g., sodium hydroxide, to give the free base, 3-phenyl-3- carbethoxytropane, which in turn can be reacted with hydrobromic acid, hydriodic acid, sulfuric acid, phosphoric acid, lactic acid, quinic acid, methanesulfonic acid, methyl iodide, allyl bromide, benzyl bromide, or o-chlorobenzyl chloride to give, respectively, the hydrobromide, hydriodide, sulfate (or bisulfate), phosphate (or acid phosphate), lactate, quinate, methanesulfonate, methiodide, allobromide, 'benzobromide, or .o-ch'lorobenzochloride salts.

EXAMPLE 7 3-Benzhydrylidenetr0pane Epoxide Hydrochloride [VII; R is CH R is H, a-series] A mixture of 36.3 g. of 3-diphenylhydroxymethyl pseudotropine hydrochloride and 500 m1. of acetic 'anhydride was refluxed for twenty hours, then cooled to room temperature and diluted with 1200 m1. of ether, whereupon there separated 20 g. of tan crystalline solid. Recrystallization of the latter material from 40 ml. of absolute methanol and 350 ml. of ether gave 3-benzhydrylidenetropane epoxide hydrochloride, MP. 265- 266" C. (dec.) (corn).

Analysis.Calcd. for CmHmNO-HCI! C, 73.77; H, 7.07; C1, 1037. Found: C, 73.63; H, 7.19; Cl, 10.40.

The free base, '3*benzhydrylidenetropane epoxide, obtained by treating the hydrochloride with aqueous sodium hydroxide, melted at 162164.5 'C. (uncorn) after recrystallization from hexane.

AnaZysis.-Calcd. for C H NO: C, 82.55; H, 7.59. Found: C, 82.10; H, 7.71.

. 11 V A mixed melting point and comparisons of the infrared spectra of the 3-benzhydrylidenetropane epoxide (or-series) just described and the 3-benzhydrylidenetropane epoxide of the fi-series described above in Example 2 indicated that the two compounds were different. The infrared spectrum exhibited no absorption characteristic of a carbonyl or hydroxyl group. The ultraviolet spectrum had a maximum at 219 m with an extinction coefficient of 12,700 plus weak absorption at 250-260 EXAMPLE 8 3-Phenyl-3-Benz0yltropane [VIII; R is CH R is H, a-series] A stirred mixture of 2.0 g. of 3-benzhydrylidenetropane epoxide hydrochloride (Ct-SEYlBS, Example '7), 2.0 ;g. of fused, powdered zinc chloride and 11 ml. of acetic anhydride was heated on a steam bath for one and onehalf hours, then cooled and poured into excess aqueous sodium hydroxide. The product was extracted with methylene dichloride and the extracts were decolorized with activated charcoal, dried and concentrated. The

:residual oil was boiled with 100 ml. of hexane, filtered,

"and the filtrate cooled to give additional solid which was removed by filtration. The second filtrate was concentrated, and the residue was dissolved in ether and treated with an excess of alcoholic hydrogen chloride. A gum separated which upon warming with acetone formed a crystalline solid. The latter was recrystallized from a methanol-ether mixture to give 3-phenyl-3-benzoyltropane in the form of colorless needles, M.P. 312

C. (dec.) (uncorr.).

Analysis. Calcd. for C H NOl-ICl: C, 73.77; H,

1.07; Cl, 10.37. Found: C, 73.90; H, 7.04; Cl, 10.11.

. The ultraviolet spectrum of 3-phenyl-3-benzoyltropane (at-series) showed extinction coefl'icients of 10,300 and 336 and maxima at 249 and 320 m respectively. The infrared spectrum exhibited a strong band at 6.00 i.

EXAMPLE 9 EXAMPLE 1 1 3-phenyl-3-carbethoxytr0pane [1; R is CH R is H, R is C H a-series] can be prepared from 3-pheny1-3- carboxytropane (or-series) and hydrogen chloride in ethanol according to the manipulative procedure described above in Example 6.'

V V V EXAMPLE 12 I 3-[Di(m-Anisyl)Hydroxymethyl]Psezrdotropine [vnRis CH3, a is 0011 1 A solution of 40 g. of a-ecgonine methyl ester in 500 ml..of tetrahydrofuran was added to a stirred solution of ,m-anisyl magnesium bromide (preparedfrom 187 g. "of m-anisyl bromide and 25 g. ofmagnesium) 'in 900 of ether over a period of fifteen minutes; .The .reaction mixture was stirred and refluxed overnight. 7 The reaction mixture was worked up according to the procedure described. above in Example 1, giving,54.7 g. of' '3 '[di(m'--anisyl)hydroxymethyl]pseudotropine as th hydrochloride salt. The latter had, the melting point r 1 12 236-237 C. (dec.) (unc'orn) when recrystallized from isopropyl alcohol and an isopropyl alcohol-ether mixture. Analysis.Calcd. for 'CggHzgNOa-HCII C, 65.78; H, 7.20; Cl, 8.44. Found: C, 65.84; H, 6.86; CI, 8.55.

EXAMPLE 13 3-(m-Anisyl) -3-(m-Anisoyl) Troparre [VI'II; R is CH R is OCH A stirred, cooled suspension of 54.7 g. of 3- [(manisyl)hydroxymethyl]pseudotropine hydrochloride in 150 ml. of acetic anhydride was treated all at once with 150 g. of fused, powdered zinc chloride, and the mixture was stirred at room temperature for fifteen hours. Following a procedure the same as that described above in Example 3, part (a), there was obtained 44 g. of 3-(m-anisyl)-3-(m-+anisoyl)tropane in the form of a brown oil. The infrared spectrum of this compound in chloroform solution exhibited a strong peak at 602 characteristic of an aromatic ketone. This product was used in the next reaction without further purification.

EXAMPLE l4 3 -(m-Anisyl 3- (m-Anz' syl )Isonizrosomethyl] Tropane Hydrochloride [IX; R is CH R is OCH EXAMPLE l5 S-(m-Anisyl)-3-Carboxytropane Hydrochloride [X; R is CH R is OCH A suspension of 5.0 g. of 3-(m-anisyl)-3-[(m-anisyl)- isonitrosomethyfltropane hydrochloride (Example 14) in 250 ml. of acetic acid was heated on a steam bath for two hours while a slow stream of dry hydrogen chloride was passed into the reaction mixture. The reaction mixture was then evaporated to dryness, the residue dis solved in 90 ml. of n-propyl alcohol, and the solution was filtered and treated with 9 ml. of triethylamine and 150 ml. of acetone. After standing overnight at room temperature there had formed 2.4 g. of crystalline 3-(manisyl)-3-carboxy-tropane, M.P. 235 C. (dec.) (uncorr.). The latter material was converted to its'hydrochloride salt in n-propyl alcohol solution. The resulting 3-(m- .anisyl)-3-carboxytropane hydrochloride had the M.P.

215-2175 C. (uncorn) when recrystallized from an Found: 01, 11.14.

S-(m-anisyl)-3-carboxytropane can be converted to 3-(m-hydroxyphenyl)-3-carboxytropane [X; R is CH R is OH] by refluxing it with aqueous hydrogen bromide and neutralizing the excess acid, according to the manipulative procedure in Example 90 of our co-pending parent application Serial No. 731,857, filed April 30, 1958.

' EXAMPLE 16 3-(m-Anisyl)3-Carbeth0xytropane Hydrobromide [1; R is CH R is OCH R is C H A solution of 0.18 g. of 3-(m-anisyl)-3-carboxytropane in absolute ethanol was refluxed in a slow stream of dry hydrogenchloride for fifteen hours. After removal of the solvent under vacuum, the residue was dissolved in water, the solution made basic with dilute sodium hydroxide and the product extracted with methylene dichloride. The extracts were dried and concentrated giving 3-(m-anisyl)-3-ca.rbethoxytropane in the form of an oil which was converted to its hydrobromide salt and crystallized from an ethanol-ether mixture giving 3-(manisyl)-3-carbethoxytrcpane hydrobromide, M.P. 178- 180 C. (uncorr.).

Analysis.Calcd. for C H NO I-IBr: C, 56.25; H, 6.82. Found: C, 55.66; H, 6.64.

By replacement of the 3-(m-anisyl)-3-carboxytropane in the preceding preparation by a molar equivalent amount of 3-(rn-hydroxyphenol)-3-carboxytropane, there can be obtained 3-(m-hydroxyphenyl)-3-carbethoxytropane [1; R is CH R is OH, R is C H The latter compound can be reacted with acetic anhydride, caproyl chloride, succinic anhydride, ,B-cyclopentylpropionyl chloride, benzoyl chloride, 3,4,5-trimethoxybenzoyl chloride or phenylacetyl chloride, to give, respectively, 3-(m-acetoxyphenyl)-3-carbethoxytropane, 3-(m-caproyloxyphenyl) -3-carbethoxytropane, 3- [m- B-carboxypropionyloxy) phenyl] -3-carbethoxytropane, 3-[m-( S cyclopentylpropionyloxy)phenyl]-3-carbethoxytropane, S-(m-benzoyloxyphenyl)-3-carbethoxytropane, 3-[m-3,4,5-trirnethoxybenzoyloxy)phenyl]-3-carbethoxytropane, or 3-(m-phenylacetoxyphenyl) -3 -carbethoxytropane.

EXAMPLE l7 3-(m-hydroxyphenyl)-3 (m-hydroxybenzoyl) tropane ["Jili; R is CH R is OH] can be prepared by refluxing 3-(rn-anisyl)-3-(manisoyl)tropane (Example 13) with aqueous hydrogen bromide and neutralizing the excess acid, according to the manipulative procedure in Example 90 of our co-pending parent application Serial No. 731,857, filed April 30, 1958.

EXAMPLE 18 3- (m-hydroxyphenyl) -3-[ (mJzydroxyph enyl) isonitrosol'nerhyljtropane [IX; R is CH R is CH] can be prepared from 3- (m-hydroxyphenyl) -3-(in-hydroxybenzoyl) tropane and hydroxylamine hydrochloride in pyridinealcohol solution according to the manipulative procedure described above in Example 14.

EXAMPLE 19 3-(m-hydr0xyplzenyl)-3-carb0xytr0pane [X; R is CH R is 01-1] can be prepared from 3-(m-hydroxyphenyl)- 3-[(m-hydroxyphenyl)isonitrosomethyl] tropane and acetic acid saturated with hydrogen chloride according to the manipulative procedure described above in Example 15.

EXAMPLE 20 3-(1r-. 1ydr0;cyphcnyl)-3-carbetlz0xytropane [1; R is CH R is OH, R" is C H can be prepared from 3-(mhydroxyphenyl]-3-carboxytropane in absolute ethanol saturated with hydrogen chloride according to the manipulative procedure described above in Example 16.

EXAMPLE 21 (a) Nor-ct-ecgonine methyl ester [V; R is H]. A sat urated aqueous solution of 243 g. of nortropinone hydrochloride was added rapidly with stirring to a cold, saturated, aqueous solution of 107 g. of potassium cyanide while maintaining the temperature below 25 C. The thick, white slurry of cyanohydrin [11 R is H] was stirred for one hour at room temperature, collected by ltration, pressed as dry as possible and then added immediately to tWo liters of concentrated hydrochloric acid with stirring and cooling to keep the temperature below 25 C. The reaction mixture was stirred at room temperature for fifteen hours and then concentrated under vacuum. The residue was dried by adding benzene and distilling off the benzene, and finally by heating the residue at 100 C. and 3 pressure. Esterification of the resulting 3=hydroxy-3-carboxynortropane .[-IV; R is H] was accomplished by refluxing it with 2.5 liters of metha- 1101 for twenty hours, during the first five hours of which period a rapid stream of dry hydrogen chloride was passed into the boiling solution. The reaction mixture was evaporated under vacuum, the solid residue dissolved in 550 ml. of water, the solution filtered and the filtrate treated with 480 g. of solid potassium carbonate with cooling. The solid material which separated was extracted twice with a total volume of 1.5 liters of boiling chloroform. The extracts were dried and concentrated, giving 135 g. of nor-a-ecgonine methyl ester, M.P. 142- 146 C. (uncorr.). Additional ester was isolated by further addition of potassium carbonate to the aqueous phase; 28 g., M.P. 137144 C. (uncorn). A sample when recrystallized from ethyl acetate had the M.P. 144- 147 C. (corn).

Analysis.Calcd. for C H NO C, 58.36; H, 8.16; N, 7.56. Found: C, 58.28; H, 8.14; N, 7.60.

(b) 3-(diphenylhydroxymethyl)norpsezldotropine Izy drochloride [VI; R and R are H].A solution of g. of nor-a-ecgonine methyl ester, prepared as described in part (a) above, in 1.5 liters of tetrahydrofuran was added to a stirred solution of phenyllithium (prepared from 594 g. of bromobenzene and 52.5 g. of lithium wire) in 1.5 liters of ether under a nitrogen atmosphere during a period of thirty minutes. The mixture was stirred and refluxed for three hours and then stirred at room temperature overnight. Following the same work-up procedure as that described in Example 1 there was obtained 157 g. of 3-(diphenylhydroxymethyl)norpseudotropine hydrochloride, which upon recrystallization from n-propyl alcohol had the M.P. 259.5 C. (dec.) (corn). The product was found to contain n-propyl alcohol of crystallization.

Analysis.Calcd. for C H NO .HCl. /3C H O: C, 68.93; H, 7.34; Cl, 9.69; C H O, 5.38. Found: C, 69.24, 68.93; H, 7.84, 7.53; Cl, 9.69; C H O, 5.38.

EXAMPLE 22 3-Phenyl-3-Benzoylnorzropane [VIII; R and R are H] A stirred suspension of 10 g. of 3-(diphenylhydroxymethyl)norpseudotropine hydrochloride (Example 21) in 30 ml. of acetic anhydride was treated all at once with 20 g. of fused, powdered zinc chloride. The temperature of the reaction mixture was kept at 15 C. for a few minutes and then stirred at room temperature for fifteen hours. The dark brown solution was then poured into 200 ml. of water, a few ml. of concentrated hydrochloric acid was added and the solution warmed on a steam bath until the odor of acetic anhydride was no longer detectable. The latter solution was made strongly acid with concentrated hydrochloric acid and the insoluble material which separated was extracted with methylene dichloride. The extracts were washed with sodium carbonate solution, dried and concentrated. The residue was recrystallized from ml. of n-propyl alcohol, giving 4.2 g. of 3-phenyl-3-benzoylnortropane, M.P. 209-212 C. (uncorr.).

Analysis.-Calod. for C H NO: C, 82.43; H, 7.27; N, 4.81. Found: C, 82.56, 82.70; H, 6.94, 7.33; N, 4.78.

The hydrochloride salt of 3 phenyl-3-benzoylnortropane had the M.P. 290-2915 C. -(dec.)(corr.) when recrystall'ized from an n-propyl alcohol-ether mixture.

Analysis.-Calcd. for C H NO.HC1: C, 73.27; H, 6.77; Cl, 10.82. Found: C, 73.38; H, 6.66; Cl, 10.84.

EXAMPLE 23 (a) 8-cyan0-3-phenyl-3-benz0ylnortr0pane [VIII; R is CN, R is H].-To a stirred solution of 7.1 g. of cyanogen bromide in 100 ml. of benzene at 50-55 C. was added over a period of three hours a solution of 10.0 g. of 3-phenyl-3-benzoyltropane in 250 ml. of benzene. The reaction mixture was stirred at 50'55 C. for two hours longer and allowed to stand overnight at room tempera- .ture. The reaction mixture was filtered to remove a small amount of crystalline material and the filtrate was 'seven hours.

15 evaporated todryness under vacuum. The residue was recrystallized from 100 ml. of methanol'giving 5.7 g. of 8-cyano-3-phenyl 3 benzoylnortropane, M.P. 160.5 162.5 C. (corr.) when recrystallized again from methanol.

Analysis.Calcd. for C H N O: C, 79.71; H, 6.37; N, 8.86. Found: C, 79.66; H, 6.33; N, 8.67.

(b) 3-phenyl-3-benz0ylnortr0pane [VIlI; R and R are H] .--A mixture of 1 .0 g. of 8-cyano-3-phenyl-3-benzoyl nort-ropane, obtained as described in part (a) above, and 50 ml. of concentrated hydrochloric acid Was'refluxed for The reaction mixture was concentrated to approximately two-thirds the original volume under vacuum and made basic by treatment with excess solid potassium carbonate. The oily product which separated was extracted with methylene dichloride, and the extracts dried and concentrated. The residue was recrystallized from acetone and then twice from absolute alcohol, giving 3- phenyl-3-benzoyln0rtropane, M.P. 2082l2 C., identical by mixed melting point and infrared comparison with the product obtained above in Example 22.

EXAMPLE 24 3-Phenyl-3-(Phenylisohitrosomethyl)Nortropane hydrochloride [IX; R and R are H] A mixture of 10.0 g. of 3-phenyl-3-benzoylnortropane (Examples 22, 23), 10.0 g. or" hydroxylamine hydrochloride, 35 ml. of pyridine and 250 m1. of n-propyl alcohol was refluxed for sixteen hours. The reaction mixture was concentrated under vacuum and the residue crystallized from'25 ml. of water to give 10.5 g. of 3-phenyl-3- (phenylisonitrosomethyl)nortropane hydrochloride, M.P. 286 C. (dec.) (uncorr.) when recrystallized from water.

Analysis.-Ca1cd. for C H N QHCI: C, 70.06; H, 6.76; N, 8.17. Found: C, 69.95; H, 7.34; N, 7.94.

EXAMPLE 25 3-Phenyl-3-Carb0xyn0rtr0pane Hydrochloride [X; R and R are H] EXAMPLE 26 3-Phenyl-3Carbethoxynortroptme Hydrochloride i [1; Rand R' are H, R" is 1-1 A suspension of 6.0 g. of 3-phenyl-3-carboxynortropane hydrochloride (Example 25) in 300 ml. of thionyl chloride was refluxed for seventy-five minutes. The reaction mixture was concentrated in vacuo on a water bath, care being taken that the temperature did not rise above about 30 C. The residue was warmed with a small amount of-absolute ethanol and then ether was added'to cause separation of 5.8 g. of 3-phenyl-3 carbethoxynortropane hydrochloride, M.P. 219.5 -221.5 C. (dec.)(corr.) when recrystallized from an ethanol-ether mixture.

Analysis.Calcd. for C I-I NO HCl: C, 64.96; H,

7.50; Cl, 11.99. Found: C, 64.85; H, 7.15; CI, 12.07.

' 7 Alternatively, the esterification was carried out by treatvmentof the 3-phenyl-3-carboxynortropane with alcoholic hydrogen chloride at room temperature for'several days.

. chloride.

. t6 EXAMPLE 27 8+(Z-Phenylethyl)Nor-u-Eegohine Methyl Ester Hydrochloride V; R is C H5CH C H lower-alkyl is CH;,]

A solution of 1.7 g. of nor-t-ecgonine methyl ester (Example 21), 1.9 g. of 2-phenylethyl bromide and 2.0 g.

EXAMPLE 28 8-propargylnor-u-ecgonine methyl ester [V; R is CIIECCHz] can be prepared by replacement of the 2- phenylethyl bromide in Example 27 by a molar equivalent amount of vpropargyl bromide.

EXAMPLE 29 8-[2-(p-aminophenyl) ethyl] nor-weegonine methyl ester [V; R is p-H NC H CH CI-I can be prepared by replacement of the 2-phenylethyl bromide in Example 27 by a molar equivalent amountof 2-(p-aminophenyl) ethyl chloride.

' EXAMPLE 30 8-benzyln0r-ot-ecg0nine methyl ester V; R is C H CH can be prepared by replacement of the 'Z-phenylethyl bromide in Example 27 by a molar equivalent amount of benzyl bromide.

' EXAMPLE 31 8-(3-phenylpr0pyl)nor-a-ecgonine methyl ester [V; R is C H CH CH CH can be prepared by replacement of the Z-phenylethyl bromide in Example 27 by a molar equivalent amount of 3-phenylpropyl chloride.

EXAMPLE 32 8-[2-(p-methoxyphenyl) ethyl] nor-u-ecogonine methyl ester [V; R is p-CH OC H CH CH can be prepared by replacement of the 2-phenylethyl bromidein Example 27 by a molar equivalent amount of 2-(p-methoxyphenyl) ethyl chloride.

EXAMPLE 33 8- [Z-(p-chlorophenyl) ethyl] nor-u-eegonine methyl ester [V; R is pClC H CI-I CH can be prepared by replacement of the 2-phenylethyl bromide in Example 27 by a molar equivalent amount of 2-(p-chlorophenyl)ethyl EXAMPLE 34 8 7 (2 Phenylethyl) 3 (Diphenylhydroxymethyl)Norpseudotropine Hydrochloride [VI;,R is C H CH CH R is H] i a A solution of 37 g. of .8-(Z-phenylethyl)nor-m-ecgonine methyl ester (Example 27);in 500 ml. of ether was added to a stirred solution of phenyllithium (prepared from 157 g. of bromobenzene and 13.9 g. of lithium'wire) in 1 liter of ether over a period of fifteen minutes. The mixture was stirred and refluxed for four hours and then stirred over- The reaction mixture was scribed above in Example 1, giving 40.5 g. of 8-(2-phenylethyl)-3-(diphenylhydroxymethyl)norpseudotropine hydrochloride, M.P. 271.5-274" C. (dec,) (co'rr.) after recrystallization from methanol-ether.

Analysis.--Calcd. for C H NO l-ICl: C, 74.73; H, 7.17; Cl, 7.89. Found: C, 74.48; H, 7.18; Cl, 7.67.

1 7 EXAMPLE 35 8-pr0pargyl-3- (Diphenylhydroxymethyl) norpseudotrop- V ine [VI; R is CHECCHZ, R" is H] can be prepared by replacement of the 8-(2-phenylethyl)nor-u-ecgonine methyl ester in Example 34 by a molar equivalent amount of 8- propargylnor-a-ecgonine methyl ester.

EXAMPLE 36 8 [2 (p aminophenyl) ethyl] 3 (diphenylhydroxymethyl)norpseudotropine [VI R is p-H NC H CH CH R is H] can be prepared by replacement of the 8-(2- phenylethyl)nor-a-ecgonine methyl ester in Example 34 by a molar equivalent amount of S-[Z-(p-aminophenyl) ethyl]nor-a-ecgonine methyl ester.

EXAMPLE 37 8 benzyl-3-(diphenylhydroxymethyl) norpseudotropine [VI; R is C H CH R is H] can be prepared by replacement of the 8-(2-phenylethyl)nor-a-ecgonine methyl ester in Example 34 by a molar equivalent amount of 8-benzylnor-a-ecgonine methyl ester.

EYAMPLE 38 8 [2 p metlzoxyphenyl) ethyl] -3-(dz'phenylhydroxymet/ I) norpseua'otropine [Vl; R is p-CH OC H Cl-I CH R is H] can be prepared by replacement of the 8-(2- phenylethyl)nor-a-ecgonine methyl ester in Example 34 by a molar equivalent amount of 8-[2-(p-methoxypheuyl) ethylflnor-a-ecgonine methyl ester.

EXAMPLE 40 8 [2 (p chlorophenyl)ethyl] 3 (diphenylhydroxymethyl) norpseudotropine [Vl; R is R is H] can be prepared by replacement of the 8-(2- phenylethyl)nor-a-ecgonine methyl ester in Example 34 by a molar equivalent amount of 8- [2-.(p-chlorophenyl)- ethyl]nor-t x-ecgonine methyl ether.

EXAMPLE 41 8-(2-Phenyl eth yl) -3-Phenyl-3-Benz0yln0rtr0pane [VIII;

R is C6H5CH2CH2, R is A stirred suspension of 35.5 g. of 8-(2-phenylethyl)-3- (diphenylhydroxymethyl)norpseudotropine hydrochloride (Example 34) in 256 ml. of acetic anhydride was treated all at once with 35.5 g. of fused, powdered zinc chloride, and the mixture was stirred at room temperature for twenty hours. The reaction mixture was worked up according to the manipulative procedure described above in Example 3, giving 28.0 g. of 8-(2-pnenylethyD-3- phenyl-S-benzoylnortropane in the form of an oil, which after crystallization and recrystallization from hexane Was obtained in the form of colorless needles, M.P. '1 12-114 C. (uncorr.).

Analysis.-Calcd. for C H NO: N, 3.54. Found: N, 3.53.

The hydrochloride salt of 8-(2-phenylethyl)-3-phenyl- 3-benzoylnortropane was prepared in the usual manner by treatment of an ethereal solution of the free base with an excess of ethanolic hydrogen chloride. The hydrochloride had the M.P. 266-267 C. (dec.) (uncoriz) when recrystallized from absolute ethanol.

Analysis.Calcd. for C H NQHCI: C, 77.85; H, 7.00; Cl, 8.21. Found: C, 77.80; H, 6.68; Cl, 8.13.

droxymethyl norpseudotropine.

l8 EXAMPLE 42 CHECCH R is H] can be prepared by replacement of the 8-(2-phenylethyl)-3-(diphenylhydroxymethyl)norpseudotropine' hydrochloride in Example 41 by a molar equivalent amount of 8-propargyl-3-(diphenylhydroxymethyl) norpseudotropine.

EXAMPLE 43 8 [2 (p amin0phenyl)ethyl] 3 phenyl- 3 benzoylzwrtropane [Vlll; R is p-H NC H CH CH R is H] can be prepared by replacement of the 8-(2 phenylethyl)- 3 diphenylhydroxymethyl norpseudotro pine hydrochloride in Example 41 by a molar equivalent amount of 8-[2- (p aminophenyl)ethyl] 3 (diphenylhydroxymethyD- norpseudotropine.

EXAMPLE 44 8-5enzyl-3-plzenyl-3-benzoylnortropane [VllI; R is C H CH R is H] can be prepared by replacement of the 8 (2 phenylethyl) 3 (diphenylhydroxymethyl)- 'norpseudotropine hydrochloride in Example 41 by a molar equivalent amount of 8-benzyl-3-(diphenylhydroxymeth- 'yl) norpseudotropine.

EXAMPLE 45 8 (3 phenylpropyl) 3 phenyl 3 benzoylnortropane [VlII; R is C H CH CH CH R is H] can be prepared by replacement or the 8-(2-phenylethyl)-3-(diphenylhydroxymethyl)norpseudotropine hydrochloride in Example 41 by a molar equivalent amount of 8-(3-phenylpropyl -3- diphenylhydroxymethyl norpseudotropine.

' EXAMPLE 46 l u 8 [2 (p methoxyphenyl)ethyl] 3 phenyl 3 benzoylnortropane [Vlll; R is p-CH OC H CH CH ,'R is H] can be prepared by replacement of the 8-(2-pheny1- ethyl) -3 -(diphenylhydroxymethyl norpseudotropine hydrochloride in Example 41 by a molar equivalent amount of 8 [2 (p methoxyphenyDethyl] 3 (diphenylhy- EXAMPLE 47 8 [2 (p chlorophenyl) ethyl] 3 phenyl 3 benzoylnartropane [VIII; R is p-ClC H CH CH R" is H] can be prepared by replacement of the .8-(2phenylethyl')- 3-(diphenylhydroxymethyl)norpseudotropine hydrochloride in Example 41 by'a molar equivalent amount of 8 [2 (p chloropheny1)ethyl] 3 (diphenylhydroxymethyl)norpseudotropine.

EXAMPLE 48 8 (Z-Phenylethyl)-3-Phenyl-3-(Phenylisonitrosomethyl)- Nortropane Hydrochloride ['IX; R is C H CH CH R is H] A mixture of 2.0 g. of 8-(2 phenylethyl)-3-phenyl-3- benzoylnortropane hydrochloride (Example 2.0 g. of hydroxylamine hydrochloride, 10 ml. of pyridine and 50 m1. of absolute ethanol was refluxed for fifteen hours. The crystalline material which had separated Was collected by filtration and Washed with water and with alcohol, giving 1.8 g. 8-(2-.phenylethyl)-3-phenyl-3 (phenylisonitrosomethyl)nortropane hydrochloride, M.P. 313- 315' C. (uncorn) when recrystallized from dimethylformamide.

Analysis.,-Calcd. for C H N O.HCl: C, 75.23; H, 6.99; Cl, 7.93. Found: C, 75.40; H, 6.68; Cl, 7.91.

EXAMPLE 49 8 proparagyl 3 phenyl 3 (phenylisonitrosomethyl)n0rtr0pane [lX; R is CHECCHZ, R is H] can be prepared by replacement of the 8-(2-phenylethyl)-3- .phenyl-3-benzoylnortropane hydrochloride in Example 48 by a molar equivalent amount of 8-propargyl-3-phenyl- 3-benzoy1nortropane.

F 19 7 EXAMPLE so l V 8 [2 (p aminpphenyl) ethyl] r 3 plienyl 3 (phen- "yli sonitrosomethyh nortropane [IX; R is V H] can be prepared by replacement of the 8-(2- phenylethyl) 3 phenyl 3 benzoylnortropane hydrochloride in Example 48 by a molar equivalent amount ,of 8 [2 .(p aminophenyl)ethy1] 3 phenyl 3 benzoylnortropane.

- EXAMPLE 51 8 g benzyl 3 phenyl 3 (phenylisonitrosomethyl)- 'nortr'opane [IX; R is C H CH R is H] can be prepared 'byreplacement of the 8-(2-phenylethyl)-3-phenyl-3-benzoylnortropane hydrochloride in Example 48 by a molar 7 equivalent amount of 8-benzyl-3-phenyl-3-benzoylnortropane. i 7

EX MPLE 52 V 8 (3 ph enylpropyll- 3 Q p henyl 3 (phnylisonitrosomethyl) niortropane"[IX; R is C H CH CH CH R is H] can'beprepared by replacementof the 8-(2-phenylethyl) -3 -phenyl-3-benzoylnortropane hydrochloride in Example 48 by a molar equivalent amount of 8-(3-phenyl- 'propyl)-3-phenyl-3-benzoylnortr0pane.

A EXAMPLE 53 i 8- [2- (p met hoxyphenybet hyl] 3 phenyl 3- -(pheitylisonitrosomethyl) norotropane [IX; R is 7 R is H] can be prepared by replacement of the 8-(2- phe'nyl'ethyl) -3 -phenyl-3-benzoylnortropane hydrochloride in Example 48 by a molar equivalent amount of 8-[2-(pmethoxyphenyl) ethyl] -3phenyl-3 -benzoylnortropane.

- EXAMPLE 54 i 8 [2 J (p chlorophenyl) ethyl] 3 phenyl 3 (phen ylisonitrosomethyl) nortropane [IX; R is R is" 1 1] can be prepared by replacement of the 8-(2- phenylethyl)-3 phenyl-3-benzoylnortropane hydrochloride in Example 48 by a molar equivalent amount of 8-[2-(pchlorophenyl) ethyl] -3 -phenyl-3 b enzoylnortrop ane.

7 EXAMPLE 55 I 8-(2-Phenylethyl) -3-Phe;zyl-3-Carb0xynortropane Hydro A suspension of 6 g. of 8-2-phenylethyl)-3-phenyl-3- (phenylisonitrosomethyl)nortropane hydrochloride (Example 48) and 75 ml. :of acetic acid was saturated with dry hydrogen chloride at C. The reaction mixture was enclosed in a pressure bottle and heated on a steam bath for fifteen hours. .ing to the manipulativeprocedurefdescribed above in Example 5, giving 4.6 g. of 8-(2 -phenylethyl)-3-phenyl-3- carboxynortropane hydrochloride, M.P. 224-2245 C.

.(uncorn) when recrystallized from a methanol-ether mix- .ture.

Analysis.Calcd. for C22H25NO2.HC1Z C, 71.05; H, 7.05; Cl, 9.53; N, 3.77. Found: C, 70.87; H, 6.99; CI, 9.37;vN, 3.81. V.

7 EXAMPLE 56 8 pr0pargyl-3-phenyl-3-carboxynortr0pane' [X; R is ,CHECCH R is H] can be prepared by replacement of the S-(Z-phenylethyl)-3-phenyl-3-(phenylisonitrosm methyl)nortropane hydrochloride in Example 55 by a molar equivalent amount of 8-propargyl-3-pheriyl-3- (phenylisonitrosomethyl)nortropane. 1

The mixture was worked up accord-' 20 EXAMPLE 57 8 [2-(p-aminophenyl)ethyl]-3-phenyl-31carb0xyn0rtropane [X; R is p-H2NC5H4CH2CHg, R is H] can be prepared by replacement of the 8-(2-pheny1ethy1)-3-phenyl-3-(phenylisonitrosomethyl)nortropane hydrochloride in Example by amolar equivalent amount of 8-[2-(paminophenyl)ethyl] 3-phenyl-3-(phenyl-isonitrosomethyl)nortropane. EXAMPLE 58 8 benzyl 3 phenyl 3 carboxynortropane [X; R is C H Cl-l R is H] can be prepared by replacement of the 8-(2-phenylethyl)-3-pheny1-3-(phenylisonitrosomethyl)nortropane hydrochloride in Example 55 by a molar equivalent amount of 8-benzyl-3-phenyl-3-(phenylisonitrosomethynnortropane.

EXAMPLE s9 8-(3-phenylpr0pyl)-3-phenyl-3-carb0xyn0rtr0pane [X; R is C H CH CH CH' R is H] can be prepared by replacement of the 8-(2-pheny1ethyl)-3-pheny1-3-(phenylisonitrosomethyl)nortropane hydrochloride in Example 55 by a molar equivalent amount of 8-(3-phenylpropyl)-3- .phenyl-3- phenylisonitrosomethyl) nortropane.

7 EXAMPLE 60 e 8 [2 (p methoxyphenyl)thyl]-3-phenyl-3-carb0xyno'rtropane [X; R is p-CH OC H CH CH R is H] can be prepared by replacement of the 8-(2-phenylethyl)-3- phenyl-3-(phenylisonitrosomethyl) nortropane hydrochloride in Example 55 by a molar equivalent amount of 8- [2 (p methoxyphenyl)ethyl];3-phenyl-3-(phenylisonitrosomethyl)nortropane.

EXAMPLE 61 A mixture of 3.3 g. of 8-(2-phenylethyl)-3-phenyl-3- 'cauboxynortropane hydrochloride (Example 55) and 100 ml. of absolute ethanol was saturated with dry hydrogen chloride at 0 C. and kept 'at room temperature for six days. Evaporation of the solvent and recrystallization of the residue from a methanolrether mixture, using acti- Vated charcoal for decolo'r-izin'g purposes, gave 2.3 g. of 8 (2-phenylethyl)-3-phenyl-3-carbethoxynortropane hydrochloride, M.P. l9 8-199.5 C. (corn).

Analysis.Calcd.'for C H NO .HCl: C, 72.07; H,

' 7.56; Cl, 8.87. -Found: 'C, 72.07; H,' 7.55; Cl, 9.05.

This application is a division of our copending application, Serial No. 731,857; filed April 30,.1958.

We claim;

1. A compound selected from the :group consisting oi A) 3-bis(monocarbocyclic ary1)methylenetropanes of the wherein R is a member of the group consisting of hydrogen, lower-aliphatic hydrocarbon, monocarbocyclic aryl-lower-aliphatic hydrocarbon, and monocanbocyclic arylamino-lower-aliphatic hydrocarbon, the monocarbocyclic aryl in each instance being selected from the group consisting of phenyl and phenyl substituted by from one to three substituents selected from the group consisting of hydroxy, fiuoro, chloro, bromo, iodo, nitro, amino, lower-alkoxy and lower-alkylamino; and R is a member of the group consisting of hydrogen and lower-alkoxy; (B) acid-addition salts thereof; and (C) lower-alkyl, lower-alkenyl and monocanbocyclic aryl-lower-alkyl quaternary ammonium salts thereof.

2. 3-benzhydrylidenetropane epoxide.

3. An acid-addition salt of 3-benzhydrylidenetropane epoxide.

4. 3-benzhydrylidenetropane epoxide hydrochloride.

5. The process for preparing a 3-bis(monocarbocyclic aryDmethylenetropane of the formula CHr-CH-OH: 011 6 Bataan on I|y which comprises treating with zinc chloride and acetic anhydride at about room temperature for about one to two hours a compound having the formula wherein R is a member of the group consisting of hydrogen, lower-aliphatic hydrocarbon, monocaubocyclic aryllower-aliphatic hydrocarbon, and monocarbocyclic arylamino-lower-aliphatic hydrocarbon, the monocarbocyclic aryl in each instance being selected from the group consisting of phenyl and phenyl substituted by from one to three substituents selected from the group consisting of hydroxy, fiuoro, chloro, hromo, iodo, nitro, amino, lower-alkoxy and lower-alkylamino; and R is a member of the group consisting of hydrogen and lower-alkoxy.

6. The process for preparing 3-benzhydrylidenetropane epoxide which comprises treating 3-(d-iphenylhydroxymethyDpseudotropine with zinc chloride and acetic anhydride at about room temperature for from about one to two hours.

No references cited.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. $058984 October To 1962 Sydney Archer et al,

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 4 lines 47 to 52, formula XV should appear as shown below instead of as in the patent:

CH CH --CH column 8, line 43, for "C, 3232" read (1 82.32 column 17, line 47, for "ether" read ester column 19, line 52 for "C H CH CH read C H CH CH column 21 lines 18 to 25, the formula should appear as shown below instead of as in the patent: R

CHM

Signed and sealed this 10th day of December 1963 (SEAL) Attest:

EDWEN L. REYNOLDS I cting Commissioner of Attesting Officer Pqaipe z'ew ERNEST W SWIDER 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (A) 3-BIS(MONOCARBOCYCLIC ARYL) METHYLENETROPANES OF THE FORMULA WHEREIN R IS A MEMBER OF THE GROUP CONSISTING OF HYDROGEN, LOWER-ALKPHATIC HYDROCARBON, MONOCARBOCYCLIC ARYL-LOWER-ALIPHATIC HYDROCARBON, AND MONOCARBOCYCLIC ARYLAMINO-LOWER-ALIPHATIC HYDROCARBON, THE MONOCARBOCYCLIC ARYL IN EACH INSTANCE BEING SELECTED FROM THE GROUP CONSISTING OF PHENYL AND PHENYL SUBSTITUTED BY FROM ONE TO THREE SUBSTITUENTS SELECTED FROM THE GROUP CONSISTING OF HYDROXY, FLUORO, CHLORO, BROMO, IODO, NITRO, AMINO, LOWER-ALKOXY AND LOWER-ALKYLAMINO; AND R'' IS A MEMBER OF THE GROUP CONSISTING OF HYDROGEN AND LOWER-ALKOXY; (B) ACID-ADDITION SALTS THEREOF; AND (C) LOWER-ALKYL, LOWER-ALKENYL ADN MONOCARBOCYCLIC ARYL-LOWER-ALKYL QUATERNARY AMMONIUM SALTS THEREOF. 